G Protein-Coupled Receptor 30 Mediates Estrogen-Induced Proliferation of Primordial Germ Cells Via EGFR/Akt/β-Catenin Signaling Pathway

In vertebrates, estrogens are required for the normal development and function of postnatal gonads. However, it remains unclear whether estrogens are able to modulate development of the fetal germ cells. Here, we show that, unexpectedly, chicken primordial germ cells (PGC) lacking estrogen receptor alpha/beta still proliferate in response to 17 beta-estradiol (E-2). This is due to the capacity of G protein-coupled receptor 30 (GPR30), existing on PGC, to directly bind E-2. Knockdown experiments suggest that GPR30 is required for E-2-stimulated PGC proliferation. Furthermore, this estrogen-induced activation of GPR30 is revealed to occur through the G beta gamma-subunit protein-dependent and through the matrix metalloproteinase-dependent transactivation of the epidermal growth factor receptor. Epidermal growth factor receptor activation results in a series of intracellular events, including activation of the phosphatidylinositol 3-kinase/serine-threonine kinase/beta-catenin pathway, which are followed by the induction of c-fos, c-myc, cyclin D1/E, and B-cell lymphoma 2 expression, and the inhibition of B-cell lymphoma 2-associated X protein expression and caspase3/9 activity. This eventually leads to decreased apoptosis and increased PGC proliferation. Collectively, these findings offer novel insights into the dynamic mechanism of estrogen action on PGC proliferation and suggest that E-2/GPR30 signaling might play an important role in regulating fetal germ cell development, particularly at the stage before sexual differentiation. (Endocrinology 153: 3504-3516, 2012)